This invention is particularly concerned with blood coagulation and ways in which coagulation assists in maintaining the integrity of mammalian circulation after injury, inflammation, disease, congenital defect, dysfunction or other disruption. Clot formation involves the conversion of fibrinogen to fibrin which polymerizes into a network to restore hemostasis after injury. A similar process results in occluded blood vessels in thrombotic diseases. The conversion of fibrinogen to fibrin is catalyzed by thrombin, the end product of a series of reactions in the blood coagulation cascade. Factor Xa, a serine protease, is the sole enzyme responsible for sustained thrombin formation in the vasculature. Thus, inhibition of factor Xa is considered to be an efficient anticoagulant strategy.
U.S. Pat. Nos. 6,376,515 B2 and 6,835,739 B2, the contents of which are incorporated herein by reference, disclose a specific factor Xa inhibitor compound, [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide (Compound A), which has the following structure:

Since treatment for diseases such as acute coronary syndromes might require co-administration of an anticoagulant agent and an antiplatelet agent, a combination would allow for increased efficacy as well as superior patient compliance during chronic treatment. However, some current anticoagulants therapies are not suitable for combination therapy. For example, warfarin, a currently available anticoagulant for chronic use, requires dose titration using international normalized ratio (INR) clotting assays to avoid excessive blood thinning and the risk of bleeding. Therefore it cannot be used as a combination with an antiplatelet agent at a fixed dose. Further, while some anticoagulant agents and antiplatelet agents may be suitable for combination therapy, they do not provide sufficient therapeutic benefit. For example, a recent clinical study examined patients on fondaparinux (an anticoagulant agent) and either aspirin or clopidogrel. The patients continued to experience thrombotic events over the course of the study. (Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, et al, N. Engl. J. Med. 2006, 354(14):1464-76).
Thus, there is a need for combination therapies that combine a fixed dose of anticoagulant agent with an antiplatelet agent that have enhanced efficacy. Further, there is a need for combination therapies for patients having thrombotic disease(s) with other co-existing conditions, such as high blood pressure or inflammation.